(a) Field
The subject matter disclosed generally relates to novel amino acid ester compounds comprising at least one nitric oxide releasing group and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one amino acid ester compound comprising at least one nitric oxide releasing group and/or at least one therapeutic agent.
The invention also provides novel compositions comprising at least one amino acid ester compound and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one amino acid ester compound which is optionally substituted with at least one nitric oxide releasing group and/or at least one therapeutic agent. The invention also provides methods for (a) treating cardiovascular diseases; (b) treating renovascular diseases; (c) treating diabetes; (d) treating diseases resulting from oxidative stress; (e) treating endothelial dysfunctions; (f) treating diseases caused by endothelial dysfunctions; (g) treating cirrhosis; (h) treating pre-eclampsia; j) treating osteoporosis; (k) treating nephropathy; (l) reperfusing injury following ischemia; and/or (m) preserving tissues, organs, organ parts and/or limbs.
The nitric oxide releasing group is preferably a nitro group (i.e. NO2,), a nitroso group (i.e. NO) and/or a heterocyclic nitric oxide donor group. The alphatic nitric oxide donor group is preferably:(CH2)n—ONO2 but can be aromatic or combinations thereof.
(b) Related Prior Art
Normal metabolic processes in vascular cells are associated with the generation of reactive oxygen intermediates that must be neutralized in order to limit oxidative damage and cellular dysfunction. In the setting of common disorders or in the presence of common risk factors for numerous diseases reactive oxygen species (ROS) are generated in abundance and their rate of synthesis and flux typically exceeds the capacity of endogenous antioxidant mechanisms. For example, hypercholesterolemia, hyperglycemia (Keeney et al, Circulation, 99: 189-191 (1999)), cigarette smoking, hyperhomocysteinemia, hypertension, and atherosclerosis are all accompanied by an increase in plasma and tissue ROS generation.
Numerous drugs for vasodilation act through a nitric oxide creating effect, for examples nitroglycerin for angina pectoris, isosorbide mono and dinitrates for long term prevention and relief of angina pectoris, sodium nitroprusside for eclempsia, and phosphodiesterase inhibitors for erectile dysfunction. However most of these molecules have fairly high levels of toxicity and or other problems with limited efficacy or side effects. Nitric oxide donating esters of amino acids have high bioavailability, low toxicity levels and their release profiles can be modified through either the length of the ester linkage (n=1 to 10) or the amino acid selected.